Amides of pyrrolidinoethylamine which can be used in lung therapy

ABSTRACT

New chemical compounds, which are pyrrolidinoethylamine amides, in the form of free bases and salts thereof, which are useful as antitussives, pharmaceutical compositions thereof, and method of treating therewith. 
     In the form of their salts, the compounds have the formula: ##STR1## wherein ##STR2## is an acyl radical of a phenylacetic,α-phenyl-α-ethylacetic, diphenylacetic, benzilic, α-lower-alkoxy-α,α-diphenylacetic, 10-phenothiazinecarboxylic, benzoic, halobenzoic, 3-coumarincarboxylic, 9-xanthenecarboxylic, salicylic, cresotic, halocresotic, lower-alkoxybenzoic, phenoxyacetic, phenoxyisobutyric, halophenoxyisobutyric, cinnamic, or 9-fluorene carboxylic acid, and wherein R&#39;H represents an inorganic or organic acid, and wherein R may be, for example, a substituted aromatic ring of the formula: ##STR3## wherein R 1  and R 2  may independently be lower-alkyl, lower-alkoxy, hydrogen, lower-alkenyloxy, or lower-alkynyloxy, and X may be hydrogen or halogen. 
     Medicaments containing these active principles may be used, inter alia, in the treatment of coughs and respiratory complaints.

This is a division of application Ser. No. 714,764, filed Aug. 16, 1976,now U.S. Pat. No. 4,122,199, issued Oct. 24, 1978.

BACKGROUND OF INVENTION

(1) Field of Invention

New chemical compounds, pyrrolidinoethylamine amides, antitussives,compositions thereof, method of treating therewith.

(2) Prior Art

Much research work has been carried out in the search for nonmorphinederivatives which have antitussive properties. In this field, manystructures have been studied and numerous patents and publications existcovering terpene molecules, dialkylamino-alkoxy-ethanol esters, andpiperazine and piperidine derivatives. Numerous of these have beenpublished during the last few years. On the other hand, few patents orarticles mention pyrrolidine derivatives, especially of the typepresently concerned, although new and useful antitussives, especially ofa nonaddicting nature, would surely still be highly desirable.

SUMMARY OF THE INVENTION

The present invention relates to certain new chemical compounds, whichare pyrrolidinoethylamine amides, in the form of free bases and saltsthereof, which are useful as antitussives, pharmaceutical compositionsthereof, and method of treating therewith.

In the form of their salts, the compounds have the formula: ##STR4##wherein ##STR5## is an acyl radical of a phenylacetic,α-phenyl-α-ethylacetic, diphenylacetic, benzilic,α-lower-alkoxy-α,α-diphenylacetic, 10-phenothiazinecarboxylic, benzoic,halobenzoic, 3-coumarincarboxylic, 9-xanthenecarboxylic, salicyclic,cresotic, halocresotic, lower-alkoxybenzoic, phenoxyacetic,phenoxyisobutyric, halophenoxyisobutyric, cinnamic, or 9-fluorenecarboxylic acid, and wherein R'H represents an inorganic or organicacid, and wherein R may be, for example, a substituted aromatic ring ofthe formula: ##STR6## wherein R₁ and R₂ may independently belower-alkyl, lower-alkoxy, hydrogen, lower-alkenyloxy, orlower-alkynyloxy, and X may be hydrogen or halogen.

OBJECTS

It is accordingly an object of the present invention to provide certainnovel pyrrolidinoethylamine amides, acid addition salts thereof,pharmaceutical compositions of the same in the form of either the freebase or an acid addition salt thereof, and a method of treatingtherewith, especially a method of treating or ameliorating coughtherewith. Another object is the provision of novel antitussive agents,compositions thereof, and method of treating therewith. Still otherobjects will become apparent hereinafter and additional objects will beobvious to one skilled in the art.

THE INVENTION

The invention, then, comprises (a) pyrrolidinoethylamine amides of theformula: ##STR7## wherein RCO is as previously defined, and (b) acidaddition salts thereof. R is preferably a 9-xanthenyl,10-phenothiazinyl, diphenyl-CH--, diphenyl-C(OH)--, or phenyl-CH(C₂H₅)-- radical, being derived respectively from 9-xanthenecarboxylic,10-phenothiazinecarboxylic, diphenylacetic, diphenylhydroxyacetic, andalpha-phenyl-alpha-ethylacetic acids. The acid addition salt may be ofany of the usual types of acid, organic or inorganic, but from thestandpoint of improved lipid solubility and flavor is preferably of thelipophilic type, e.g., a fatty acid of 14-22 carbon atoms, inclusive,e.g., palmitic, linoleic, linolenic, or oleic, or of the naphthoic type,especially pamoic, particularly when R has one of the preferred meaningsassigned in the foregoing. When R has formula II as previously assigned,then R₂ is preferably allyloxy, hydroxy, or carboxy, R₁ is preferablymethyl or hydrogen, and X is preferably bromine or hydrogen, or allthree are methoxy.

These new chemical compounds forming an object of the invention can beobtained by the following methods, as illustrated by the followingexamples:

1st method

The acid chloride ##STR8## is reacted with the pyrrolidinoethylamine inan organic solvent, for instance benzene or acetone.

2nd method

The pyrrolidinoethylamine is heated in the presence of a lower-alkylester, for instance ##STR9## sodium is used as catalyst.

For sake of convenience, the compounds are at times designated by theircode number.

DETAILED DESCRIPTION OF THE INVENTION

The following Examples are given by way of illustration only and are notto be construed as limiting.

EXAMPLE 1 (illustrates method 2) Synthesis ofN(2'-pyrrolidino-ethyl)-9-fluorene-carboxamide hydrochloride (F 1532)

One mol (238 g) of ethyl 9-fluorene carboxylate is treated with 1.6 molof 2-amino-ethyl pyrrolidine. Heated for 2 hours at 150° C., the ethanoldistills over as it is formed. The reaction mass obtained is dissolvedin methylene chloride, washed three times with water, dried, filteredand distilled to dryness.

The base is then hydrochlorided in solution in a mixture of ethanol andmethylene chloride.

The hydrochloride is precipitated by the addition of ether. The yield ofhydrochloride (F 1532) referred to the ethyl ester is 85%.

Developed Formula ##STR10## Empirical formula: C₂₀ H₂₃ ClN₂ O Molecularweight: 342.9

White crystals

Melting point: 198° C.

Plate chromatography:

support: silica Merck G 254

solvent: butanol/acetic acid/water 6/2/2

development: ultraviolet lamp or iodine vapors

Rf: 0.64

Infrared spectrography:

absorption band

ν_(C)═O amide at 1675 cm⁻¹

ν_(C)═C aromatic at 1610 cm⁻¹

ν_(C--H) aromatic at 3070 cm⁻¹

Solubility characteristics: very soluble in water, ethanol and propyleneglycol.

EXAMPLE 2 (illustrates the 1st method)N(2'-pyrrolidino-ethyl)-9-xanthene carboxamide hydrochloride (F 1534)

The chloride of 9-xanthene carboxylic acid is obtained by treating 1 molof acid, suspended in benzene, with thionyl chloride and then distillingto dryness. The crude acid chloride, dissolved in ether, is treated witha stoichiometric amount of N-2-pyrrolidino-ethyl amine. The F 1534precipitates as it is formed. Purification is effected by treatment withan excess of bicarbonate to form the base of 1534, which is extracted bymethylene chloride, and then rehydrochlorided by an ethanolic solutionof hydrochloric acid.

The yield of crude product is 85% and of pure product 70%.

Developed Formula ##STR11## Empirical formula: C₂₀ H₂₂ ClN₂ O₂ Molecularweight: 357.9

Melting point: 195° C.

White crystals

Plate chromatography:

support: silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: ultraviolet lamp and iodine vapors

Rf: 0.65

Infrared spectrography:

ν_(NH) 3230 and 3200 cm⁻¹

ν_(C)═O sintered to 1645 cm⁻¹

Solubility characteristics: very soluble in water. 10% soluble inethanol and propylene glycol.

EXAMPLE 3 Synthesis of N(2'-pyrrolidino-ethyl)-α-phenyl-α-ethylacetamide hydrochloride (F 1419)

To a solution of 1 mol of α-phenyl-α-ethyl acetyl chloride in 2 litersof benzene add, with agitation, a benzene solution of 1 mol of2-pyrrolidino-ethyl amine. The hydrochloric acid formed duringcondensation attaches itself to the pyrrolidine group and the expectedderivative crystallizes out in the reaction medium.

In order to favor the precipitation, ether may be added.

The yield of the reaction is quantitative for product of the formula:##STR12## Empirical formula: C₁₆ H₂₅ ClN₂ O Molecular weight: 296.8

White crystals, slightly hygroscopic

Melting point: 160° C.

Plate chromatography:

support: silica gel Merck G 254

solvent: butanol/acetic acid/water 6/2/2

development: ultraviolet lamp or iodine vapor

Rf: 0.44

Infrared spectrography: absorption band at 1645 cm⁻¹ of the C═O amide.

Solubility characteristics: very soluble in water, insoluble in ether.15% soluble in ethanol, 25% in propylene glycol and 7% in N-methylpyrrolidone.

EXAMPLE 4 N(2'-pyrrolidino-ethyl)-10-phenothiazine carboxamidehydrochloride (F 1461)

To a suspension of 1 mol of 10-chlorocarbonyl-phenothiazine in 2 litersof acetone there is slowly added a solution of 1 mol of2'-pyrrolidino-ethyl amine in acetone. After several hours at roomtemperature, the crystalline suspension is filtered, the crystals aretreated with an aqueous solution of sodium bicarbonate, followed byextraction with methylene chloride; the organic phase is then distilled;the residue is taken up in an ethanolic solution of hydrochloric acid.The F 1461 precipitates upon the addition of ether.

The yield is about 70% of a derivative of the formula: ##STR13##Empirical formula: C₁₉ H₂₂ ClN₃ OS White crystals

Melting point: 207° C.

Plate chromatography:

support: silica gel

solvent: butanol/acetic acid/water 6/2/2

development: ultraviolet lamp

Rf: 0.55

Infrared spectrography: absorption bands: ν_(NH) to 3480 cm⁻¹ andν_(C)═O to 1660 cm⁻¹.

Solubility characteristics: 10% soluble in water, ethanol, propyleneglycol and N-methyl pyrrolidone.

EXAMPLE 5 N(2'-pyrrolidino-ethyl)diphenyl acetamide hydrochloride (F1459)

Into a solution of 1 mol of diphenyl acetyl chloride in acetone there isgradually introduced with agitation 1 mol of pyrrolidino-ethyl amine inacetone solution. After 8 hours at room temperature, the acetone isdistilled to dryness.

The residual oil is treated with an aqueous bicarbonate solution andextracted with chloroform; the organic phase is distilled to dryness,and the residue is taken up in an ethanolic solution of hydrochloricacid. The yield is 60% of a derivative of the formula: ##STR14##Empirical formula: C₂₀ H₂₅ ClN₂ O Molecular weight: 344.9

White crystals

Melting point: 179° C.

Plate chromatography:

support: silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: iodine vapors

Rf: 0.51

Infrared spectrography:

Absorption bands:

ν_(NH) at 3240 and 3200 cm⁻¹

ν_(C)═O at 1675 cm⁻¹

Solubility characteristics: 25% soluble in water, 5% in ethanol, 3% inpropylene glycol.

EXAMPLE 6 N(2'-pyrrolidino-ethyl)diphenyl-α-chloroacetamidehydrochloride

An acetone solution of 1 mol of diphenyl-α-chloroacetyl chloride istreated at 0° C. with an acetone solution of pyrrolidino-ethylamine.

The derivative of the formula: ##STR15## crystallizes out as it isformed. Empirical formula: C₂₀ H₂₄ Cl₂ N₂ O

Molecular weight: 379.3

Melting point: 160° C.

EXAMPLE 7 N(2-pyrrolidino-ethyl)diphenyl-α-ethoxy-acetamidehydrochloride (F 1460)

The derivative obtained in accordance with Example 6 is treated insuspension in absolute ethanol.

After refluxing for 4 hours and concentration under vacuum, the F 1460precipitates upon the addition of isopropyl ether.

For purification it is possible to dehydrochlorinate by reaction of anaqueous bicarbonate solution and then, after extraction with chloroform,distillation and treatment with an ethanolic solution of hydrochloricacid; the purified derivative is recovered with a yield of 80%.##STR16## Empirical formula: C₂₂ H₂₉ ClN₂ O₂ Molecular weight: 389

White crystals

Instantaneous melting point: 130° C.

Plate chromatography:

support: silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: iodine vapors

Rf: 0.63

Solubility characteristics: 1% soluble in water, 4% in ethanol,insoluble in ether.

EXAMPLE 8 N(2'-pyrrolidino-ethyl)-2-allyloxy-5-bromo-3-methyl benzamidehydrochloride (F 1479)

By treating the acid chloride of the formula: ##STR17## with a solutionof pyrrolidino-ethyl amine and, after customary treatment there isrecovered, in quantitative yield, the derivative of the formula:##STR18## Empirical formula: C₁₇ H₂₄ ClBrN₂ O₂ Molecular weight: 403.7

White crystals

Melting point: 118° C.

Plate chromatography:

support: silica gel

solvent: butanol/acetic acid/water 6/2/2

development: ultraviolet lamp and iodine vapors

Rf: 0.62

Solubility characteristics: very soluble in water.

EXAMPLE 9 N(2'-pyrrolidino-ethyl)-5-bromo-3-methyl-salicylamidehydrochloride

Methyl-5-bromo-3-methyl salicylate, suspended in pyrrolidino-ethylamine, is treated at 90° C. for 4 hours. The methanol is distilled offas it is formed. The reaction mixture is then treated with 6 Nhydrochloric acid, and the initial methyl ester is extracted with ether;the aqueous phase is treated with ammonia, extracted with ether, washed,dried, evaporated to dryness, and then hydrochlorided by an ethanolicsolution of hydrochloric acid, precipitated with ether, filtered, andwashed.

The derivative of the formula: ##STR19## is recovered in a yield of 80%.Empirical formula: C₁₄ H₂₀ BrClN₂ O₂

Molecular weight: 363.7

White crystals

Melting point: 184° C.

Plate chromatography:

support: silica gel

solvent: butanol/acetic acid/water 6/2/2

development: ultraviolet lamp and iodine vapors

Rf: 0.75

Solubility characteristics: very soluble in water, 3% soluble inethanol, 7% in propylene glycol, insoluble in ether.

The following derivatives were also obtained by Methods 1 and 2.

EXAMPLE 10 N(2'-pyrrolidino-ethyl)diphenyl-hydroxy-acetamidehydrochloride (F 1535) Developed Formula ##STR20## Empirical formula:C₂₀ H₂₅ ClN₂ O₂ Molecular weight: 360.9

White crystals

Melting point: 209° C.

Plate chromatography:

support: silica gel Merck G 254

solvent: BuOH/AcOH/H₂ O 6/2/2

development: UV and iodine

Rf: 0.64

Infrared spectrography: ν_(NH) and ν_(OH) wide absorption band at 3250cm⁻¹ ν_(C)═O at 1665 cm⁻¹.

Solubility characteristics: very soluble in water.

EXAMPLE 11 N(2'-pyrrolidino-ethyl)phenyl piperidino-acetamide (F 1533)Developed Formula ##STR21## Empirical formula: C₁₉ H₂₉ N₃ O Molecularweight: 315.5

Beige crystals

Melting point: 80° C.

Infrared spectrography: _(NH) at 3350 cm⁻¹ and _(C)═O at 1665 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: UV and iodine

Rf: 0.13

Solubility characteristics: insoluble in water. Very soluble in ethanol.

EXAMPLE 12 N(2'-pyrrolidino-ethyl)-2-carboxy-benzamide (F 1537)

This derivative is obtained from phthalic anhydride in solution inacetone treated with 2-amino-ethyl-pyrrolidine. The F 1537 crystallizesout in the form of a monohydrate.

Developed Formula ##STR22## Empirical formula: C₁₄ H₂₀ N₂ O₄ Molecularweight: 280.3

Crystals of impure white color

Instantaneous melting point: 130° C.

Infrared spectrography:

ν_(NH) at 3240 cm⁻¹

ν_(C)═O (acid) low at 1710 cm⁻¹

ν_(C)═O (amide) at 1645 cm⁻¹

ν_(C)═O (internal salt COO⁻) intense at 1550 and 1600 cm⁻¹.

Plate chromatography:

support: Merck silica gel

solvent: methylethylketone/N-propanol/EtOH/NH₄ OH 34% 90/9/36/64

development: ultraviolet lamp or iodine vapors

Rf: 0.69

Solubility characteristics: very soluble in water, ethanol and propyleneglycol.

EXAMPLE 13 N(2'-pyrrolidino-ethyl)-cinnamide, HCl (F 1542) DevelopedFormula ##STR23## Empirical formula: C₁₅ H₂₁ ClN₂ O Molecular weight:280.8

White crystals

Melting point: 202° C.

Infrared spectrography:

ν_(N--H) 3260 cm⁻¹

ν_(C)═O (amide) 1670 cm⁻¹

ν_(C)═C (ethylene) 1630 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: ultraviolet lamp or iodine vapors

Rf: 0.81

Solubility characteristics: very soluble in water, ethanol, andpropylene glycol.

EXAMPLE 14 N(2'-pyrrolidino-ethyl)-3-coumarin-carboxamide hydrochloride(F 1543) Developed formula ##STR24## Empirical formula: C₁₆ H₁₉ ClN₂ O₃Molecular weight: 322.8

Beige crystals

Melting point: 220° C.

Infrared spectrography:

ν_(NH) at 3330 cm⁻¹

ν_(C)═O (lactone) 1700 cm⁻¹

ν_(C)═O amide 1660 cm⁻¹

ν_(C)═C at 1610 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: ultraviolet lamp or iodine vapors

Rf: 0.53

Solubility characteristics: very soluble in water. 4% soluble inethanol, 7% in propylene glycol.

EXAMPLE 15 N(2'-pyrrolidino-ethyl)-4-chloro-phenoxy-isobutyramidehydrochloride (F 1541) Developed formula ##STR25## Empirical formula:C₁₆ H₂₄ Cl₂ N₂ O₂ Molecular weight: 347.3

White crystals

Melting point: 140°

Infrared spectrography:

salification bands 2500 to 3500 cm⁻¹

ν_(N--H) 3230 cm⁻¹

ν_(C)═O (amide) 1660 cm⁻¹

ν_(C)═C 1600 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: ultraviolet lamp or iodine vapors

Rf: 0.57

Solubility characteristics: Soluble in water, ethanol, and propyleneglycol.

EXAMPLE 16 N(2'-pyrrolidino-ethyl)phenoxy-isobutyramide hydrochloride (F1540) Developed formula ##STR26## Empirical formula: C₁₆ H₂₅ ClN₂ O₂Molecular weight: 312.8

White crystals

Melting point: 94°

Infrared spectrography: salification bands 2500 to 3500 cm⁻¹

ν_(NH) at 3250 cm⁻¹

ν_(C)═O at 1660 cm⁻¹

ν_(C)═C at 1600 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: UV and iodine

Rf: 0.58

Solubility characteristics soluble in water, ethanol and propyleneglycol.

EXAMPLE 17 N(2'-pyrrolidino-ethyl)-4-chloro-phenoxy-acetamidehydrochloride (F 1539) Developed formula ##STR27## Empirical formula:C₁₄ H₂₀ Cl₂ N₂ O₂ Molecular weight: 319.2

White crystals

Double melting point: 95° and 144° C.

Infrared spectrography: salification bands at 2500 to 3500 cm⁻¹

ν_(NH) 3260 cm⁻¹

ν_(C)═O (amide) 1660 cm⁻¹

ν_(C)═C 1600 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: ultraviolet lamp or iodine vapors

Rf.: 0.45

Solubility characteristics: soluble in water, ethanol, and propyleneglycol.

EXAMPLE 18 N(2'-pyrrolidino-ethyl)-3-4-5-trimethoxy-benzamidehydrochloride (F 1538) Developed formula ##STR28## Empirical formula:C₁₆ H₂₅ ClN₂ O₄ Molecular weight: 344.8

Beige crystals

Melting point: 158° C.

Infrared spectrography:

Salification bands 2500 to 3550 cm⁻¹

ν_(NH) 3290 cm⁻¹

ν_(C)═O (amide) 1650 cm⁻¹

Plate chromatography:

support: Merck silica gel

solvent: BuOH/AcOH/H₂ O 6/2/2

development: UV and iodine

Rf: 0.5

Solubility characteristics: soluble in water, ethanol, and propyleneglycol.

Obtaining of New Salts

The hydrochloride derivatives described in the above examples can betreated by the following techniques in order to obtain newtherapeutically acceptable salts whose organoleptic properties, and moreparticularly flavor, are however improved.

Salification Experimental Record Method A--transalification

The water insoluble salts are prepared by addition of an aqueoussolution of one equivalent of the hydrochloride of the base to anaqueous solution of one equivalent of the sodium salt of the acid.

The salt is centrifuged, washed with water until disappearance of thechloride. Dry under vacuum to constant weight.

Method B--direct salification

The hydrochloride of the amine is treated with an aqueous solution ofsodium bicarbonate and the base is extracted with chloroform. Dry.Filter. This solution is added to a solution or suspension of the acidin chloroform.

Dissolve. Concentrate the solution and crystallize the salt by additionof ether.

Example 19 (illustrates Method A)N(2-pyrrolidino-ethyl)-α,α-diphenyl-acetamide pamoate (F 1629)

A solution of 0.15 mol of N(2-pyrrolidino-ethyl)diphenylacetamidehydrochloride in 2.5 liters of water is added to a solution of 0.075 molof sodium salt of pamoic acid in 1 liter of water.

The precipitate obtained is centrifuged, washed with water untildisappearance of the chloride, and dried under vacuum to constantweight.

The yield of the product of the following formula is 95%. ##STR29##Empirical formula: C₆₃ H₆₄ N₄ O₈ Molecular weight: 1005.23

Yellow crystals

Instantaneous melting point: 145°

Infrared spectrography:

Salification band 2500 to 3500 cm⁻¹

ν_(C)═O (amide) 1645 cm⁻¹

ν_(C)═O (COO⁻) 1565 cm⁻¹

Plate chromatography:

support: silica gel

solvent: Butanol/acetic acid/water 6/2/2

development: ultraviolet lamp or iodine vapors

Rf: acid: 0.70 (UV - FeCl₃) base: 0.35 (UV)

Solubility characteristics: Insoluble in water and alcohol.

Soluble in methyl pyrrolidone and dimethyl acetamide.

EXAMPLE 20 (Method A) N(2-pyrrolidino-ethyl)-α,α-diphenyl-acetamidepalmitate (F 1630) ##STR30## Empirical formula: C₃₆ H₅₆ N₂ O₃ Molecularweight: 564.82

White crystals

Instantaneous melting point: 55°

Infrared spectrography:

salification bands 2500 to 3500 cm⁻¹

_(NH) 3270 cm⁻¹

_(C)═0 (amide) 1645 cm⁻¹

Plate chromatography:

-support: silica gel

-solvent: butanol/acetic acid/water 6/2/2

-development: ultraviolet lamp or iodine vapors

-Rf: base: 0.35 (UV) acid: 0.85 (rhodamine+UV)

Solubility characteristics: Insoluble in water. Poorly soluble inalcohol, dimethyl acetamide, methyl pyrrolidone, and propylene glycol.

The new derivatives obtained in the foregoing manner, which are bases,can be converted into addition salts with acids, which form part of theinvention. The addition salts can be obtained by the reaction of the newderivatives with acids in suitable solvents such, for example, as shownby the examples. As acids used for the formation of these addition saltsthere may be mentioned, in the mineral series: hydrochloric,hydrobromic, methanesulphonic, sulphuric and phosphoric acid; in theorganic series: acetic, propionic, maleic, fumaric, tartaric, citric,oxalic, benzoic acid, to name a few.

The invention accordingly also relates to the salts with organic orinorganic acids, especially lipophilic acids, e.g., fatty acids having14 to 22 carbon atoms, inclusive, which are linear or branched,saturated or unsaturated, including palmitic, linoleic, linolenic, andoleic acids, and the like, as well as of the naphthoic type, especiallypamoic acid, in addition to the usual organic and inorganic acids of thetype already mentioned.

Moreover, in addition to the substituents R₁ and R₂ as specificallyillustrated by the Examples for Formula II, the same and/or additionalsubstituents as specifically shown for R₁ and R₂ may be present, and R₁may be present in a different ring position, e.g., in a differentposition of the benzene ring with respect to the R₂ and X substituentspresent therein. X may, for example, be fluoro, bromo, chloro, or iodo.Either or both of R₁ and R₂ may be, for example, methyl, ethyl, propyl,amyl, methoxy, ethoxy, propoxy, amyloxy, propenyloxy, butenyloxy,propynyloxy, butynyloxy, hydroxyethoxy, hydroxypropyloxy,hydroxybutyloxy, or hydroxyamyloxy or the like, "lower" in each casemeaning a maximum of five (5) carbon atoms in such group. The nature andlocation of these substituents depends only upon the selected startingcompound employed in the preparation thereof, as will be apparent andfully within the ability of one skilled in the art, as will selectionand preparation of the desired acid addition salt of such compound inany particular case.

EXPERIMENTAL

The high order of activity of the active agents of the present inventionhas been evidenced by tests in lower animals and representative of theseare reported herein.

A--Toxicology

The chemical compounds previously described were subjected to toxicitytests.

The acute toxicity, determined by the 50% lethal dose (DL 50), isreported in the following table.

It is determined on mice, the products being administered orally,intraperitoneally, and intraveneously in isotonic aqueous solution.

    ______________________________________                                                   DL 50 (mg/kg)                                                                            intraperi-                                              Compounds    oral     toneal    intravenous                                   ______________________________________                                        F 1419       660      200       76                                            F 1459       562      178       48                                            F 1460       750      178       40                                            F 1461       560      178       26                                            ______________________________________                                                    DL 50 (en mg/kg)                                                  Compounds     oral        intraperitoneal                                     ______________________________________                                        F 1532        178          75                                                 F 1533        750         178                                                 F 1534        750         178                                                 F 1535        562         237                                                 F 1536        1000        300                                                 F 1537        1000        500                                                 F 1538        562         300                                                 F 1539        1000        178                                                 F 1540        1000        237                                                 F 1541        562         178                                                 F 1542        1000        178                                                 F 1543        1000        178                                                 F 1629        2000        750                                                 F 1630        1500        500                                                 ______________________________________                                    

B--Pharmacology

The pharmacological experiments to which these new compounds weresubjected disclosed interesting antitussive properties upon using thecritic acid aerosol method on guinea pigs.

The animals were subjected to a 20% citric acid aerosol for 15 minutes.

The coughs were recorded by a microphone.

The products were administered intraperitoneally 20 minutes before theexposure to the aerosol.

The results are summarized in the following table.

    ______________________________________                                        Citric Acid Aerosol Method                                                    (on guinea pigs)                                                                                        % reduction of                                                  dose in mg/kp no. of coughs in                                    Lots        i.p.          15 minutes                                          ______________________________________                                        Controls    --            22                                                                            20                                                  F 1532      25            -15%                                                F 1533      50            - 7%                                                F 1534      50            -63%                                                F 1535      50            -43%                                                F 1536      50            0                                                   F 1537      50            -8%                                                 F 1538      50            -1%                                                 F 1539      50            -18,5%                                              F 1540      50            -22%                                                F 1541      50            -26%                                                F 1542      50            -19,5%                                              F 1543      50            -19%                                                F 1630      50            -60%                                                F 1629      50            -60%                                                F 1419      50            -35%                                                F 1459      50            -65%                                                F 1460      50            -20%                                                F 1461      50            -56%                                                ______________________________________                                    

Some derivatives were also tested orally. By way of example, we cite afew results as compared with the citric acid aerosol.

    ______________________________________                                                    orally        % decrease in no.                                   Compounds   doses in mg/kg                                                                              coughs in 15 mins.                                  ______________________________________                                        F 1419      100           -40                                                             50            -22                                                 F 1459      50            -31                                                 F 1461      50            -12                                                             100           -25                                                 F 1629      100           -50                                                             50            -30                                                 ______________________________________                                    

A second method using a different type of stimulation of coughs made itpossible to note, as compared with codeine, the antitussive propertiesof the main components claimed.

The technique employed is derived from Takagi's technique, and consistsin causing coughing by mechanical stimulation of the trachealbifurcation in the unanesthetized guinea pig.

The cough is evaluated by the research worker in accordance with thefollowing scale:

1: heavy cough

0.5: light cough

0: no cough

The products are administered intraperitoneally and the stimulation iseffected 10 and 20 minutes after the injection.

The results are set forth in the following table:

    __________________________________________________________________________    Takagi's Technique                                                                              Cough rating                                                                  before treatment                                                                       after treatment                                    Lots   weight                                                                            parameters                                                                           to to + 5 mn                                                                            t + 10 mn                                                                          t + 20 mn                                    __________________________________________________________________________    CONTROLS                                                                             310 no. of animals                                                                       12 12    12    12                                                      m      1,0                                                                              0,96  0,83  0,83                                                    s2     0  0,020 0,060 0,106                                                   Em     0  0,03  0,07  0,09                                         F 1459 330 no. of animals                                                                       12 12    12    12                                           50 mg/kg   m      1,0                                                                              0,96  0,67  0,33                                                    s2     0  0,020 0,106 0,151                                                   Em     0  0,03  0,09  0,11                                                    % variation     -32% S                                                                              -66%                                                                          H.S.                                         F 1461 310 no. of animals                                                                       12 12    12    12                                           50 mg/kg   m      0,87                                                                             0,79  0,54  0,37                                                    s2     0,051                                                                            0,067 0,248 0,233                                                   Em     0,06                                                                             0,07  0,14  0,14                                                    % variation     -35% N.S.                                                                           -55% S.                                      Reference                                                                            310 no. of animals                                                                       12 12    12    12                                           CODEINE    mals   0,96                                                                             0,96  0,75  0,67                                         50 mg/kg   s2     0,020                                                                            0,020 0,113 0,151                                                   Em     0,03                                                                             0,03  0,03  0,11                                                    % variation     -22% N.S.                                                                           -30% S.                                      __________________________________________________________________________     m = average of the ratings; s2 = variance; Em = difference from mean          S.:result significant                                                         N.S.:result not significant                                                   H.S.:result highly significant                                           

The determination of fungistatic bacteriostatic properties was carriedout by two methods on four strains:

Diffusion Method

The microorganisms are introduced into nutrient agar. On the surface,paper disks soaked with the products to be tested are deposited, after18 hours incubation. The diameter of the growth inhibition zones ismeasured.

Measurement of the Minimum Inhibitory Concentration (M.I.C.)

Halved serial dilutions are formed in a hemoylsis tube, in each case toa volume of 1 ml; each dilution is inoculated with 10⁶ micro-organismsper ml. After 48 hours in the oven, the minimum inhibitory concentrationis determined. A subculture of the negative tubes (bacteriostatic),makes it possible to note the bactericidal concentration. A significantaction with respect to Staphylococcus aureus and Escherichia coli wasobtained with the products F 1459, F 1532, F 1533, F 1534 with MICs ofthe order of 625 μg; a more moderate but significant effect was obtainedwith Pseudomonas aeruginosa and Candida albicans. These products areaccordingly not major antiseptics, but their bactericidal action is realand significant at concentrations of 1 g percent.

Additional Properties

Furthermore, certain derivatives showed a high order of local anesthesiaactivity comparable to that of procaine; these were F 1534, F 1535 and F1541.

The antalgic properties with respect to a decrease in contortions causedby phenyl benzoquinone, as measured in mice, are very clear from the 150mg/kg by mouth in the case of F 1534 (40% decrease), F 1539 (75%decrease), and F 1541 (60% decrease).

Compositions and Method of Treating

The foregoing properties taken together, and the low toxicity of thesecompounds, confirmed by a subacute toxicity study for six weeks on twospecies of animals, namely rats and dogs, make it possible at thepresent time to test these derivatives clinically for their use inrespiratory therapy and in the treatment of certain pains. The newderivatives thus show antitussive and, in certain cases also localanesthesia, properties sufficient to permit their use in therapy for thetreatment of laryngotracheitis, stubborn tracheitis, nervous cough, andsmoker's cough. These therapy treatments were carried out by means ofsuitable pharmaceutical forms, using either the product in its initialfree basic form or in the form of a therapeutically acceptable salt. Thenovel compounds are preferably used in the form of theirpharmaceutically-acceptable acid addition salts, e.g., theirhydrochlorides, hydrobromides, or the like. The salt form is also thebest form for pharmaceutical formulations. Innumerable otherpharmaceutically-acceptable acid addition salts can be prepared from thehydrochlorides via the free bases in conventional manner. For oral use,the compounds are usually administered as tablets, solutions, orsuspensions, in which they are present together with usualpharmaceutical carriers, excipients, binders, and the like. For example,tablets may be prepared conventionally by compounding one of the newcompounds, preferably in the form of an acid addition salt thereof, withcustomary carriers and adjuvants, e.g., talc, magnesium stearate,starch, lactose, gelatin, gums, and the like. In their most advantageousform, then, the compositions of the present invention will contain anon-toxic pharmaceutical carrier in addition to the active ingredient.Exemplary carriers are:

Solids: lactose, magnesium stearate, calcium stearate, starch, terraalba, dicalcium phosphate, sucrose, talc, stearate acid, gelatin, agar,pectin, acacia, or other usual excipient;

Liquids: peanut oil, sesame oil, olive oil, water, elixir, or otherusual excipient. The active agents of the invention can be mostconveniently administered in such compositions containing about 0.01 to67 percent, preferably 0.04 to 12.15 percent, by weight of the activeingredient. Such formulations are representatively illustrated in U.S.Pat. No. 3,402,244.

A wide variety of pharmaceutical forms suitable for many modes ofadministration and dosages may be employed. For oral administration, theactive ingredient and pharmaceutical carrier may, for example, take theform of a granule, pill, tablet, lozenge, elixir, syrup, or other liquidsuspension or emulsion; and for rectal administration, a suppository.

The method of using the compounds of the present invention comprisesinternally administering a compound of the invention, usually in theform of a non-toxic, pharmacologically-acceptable acid addition salt,and preferably admixed with a pharmaceutical carrier, for example, inthe form of any of the above-mentioned compositions, or filled into acapsule, to alleviate one or more of the foregoing enumerated conditionsand symptoms in a living animal body, whether human or domestic animal,for example, the aforementioned cough. The compounds, and especiallytheir non-toxic salts, may be advantageously employed in amounts ofabout 1 to 50 milligrams per unit dose, preferably about 2.5 to 25milligrams per unit dose, preferably and usually in admixture with theconventional carrier. The unit dose is preferably given a suitablenumber of times daily so that the daily dose may vary from about 5 toabout 100 milligrams. However, the compounds are subject to usualvariations in optimum daily and unit dosages, due to patient bodyweight, condition, and ancillary factors, and the invention thereforeshould not be limited by the exact ranges stated. The exact dosage, bothunit and daily, will of course have to be determined according toestablished veterinary and medical principles. The doses foradministration usually vary for oral and rectal administration fromabout 5 to about 100 mg over a period of 24 hours, and the activesubstances are generally administered orally in the form of capsules,tablets of normal or delayed action, syrups and drops, and rectally inthe form of suppositories or rectal capsules.

The active principles of the present invention may be used alone ortogether with or in combination with other or supplementary activeprinciples for the particular treatment involved, such asantihistamines, expectorants and bronchic fluidizers, antibiotics,corticoids, vitamins, analgesics, anticholinergics, sedatives,stimulants, buffering agents, antacids, or the like. By way ofillustration, but not of limitation, we cite a few representativegalenical preparations, which are representative for all of thepharmacologically active compounds of the invention, but which have beenparticularly designed to embody as active ingredient the particularcompounds embodied therein, especially in the form of a pharmaceuticllyacceptable salt thereof:

(a) tablets

50 mg of F 1535

excipient q.s.p.

(b) syrup

F 1629: 200 mg

Na guiacol sulfonate: 600 mg

terpene hydrate: 1 g

excipient q.s.p.

(c) suppositories

F 1534: 10 mg

Promethazine: 30 mg

excipient q.s.p.

(d) long-action tablets

F 1629: 50 mg

excipient q.s.p.

(e) syrup

F 1419

Vitamin C

antibiotic

(f) suppository

F 1459: 10 mg

General

The free bases of the invention may generally be extracted with asuitable organic solvent, e.g., ether, methyl-butyl ketone, or the like,if desired. Salts with pharmaceutically acceptable acids, e.g.,hydrochloric, hydrobromic, fumaric, citric, maleic, tartaric, or lactic,or the like, may also be precipitated with acid from a dried solution ofthe free base in a conventional manner and recrystallized, if desired(See Example 7), instead of directly, as also shown herein. One acidsalt, even if not pharmaceutically acceptable, is still useful, since itcan readily be converted to another salt which is pharmaceuticallyacceptable in known manner, e.g., by alkalization and then acidificationwith a different acid, if desired.

Where the foregoing examples produce a compound having a methyl or otherlower-alkyl group, it is to be understood that compounds containingother lower-alkyl groups of straight or branched nature and containingup to five carbo atoms, inclusive, such as methyl, ethyl, propyl,isopropyl, butyl, sec.-butyl, t.-butyl, amyl and isoamyl, are preparedin the same manner by substitution in the process of the appropriatedifferent lower-alkyl starting material. Likewise, where chloro or otherhalogen atom is present, although chlorine is preferred, further halogencompounds including iodo, bromo, chloro, and fluoro compounds areprepared starting from the appropriate halogenated starting material.Similarly, where methoxy or other lower-alkoxy group is present,compounds having other lower-alkoxy groups containing variouslower-alkyl groups having up to five carbon atoms inclusive are preparedin the same manner from the appropriate different lower-alkoxy startingmaterial. In the same manner, ortho and meta products are producedinstead of the para by utilizing the selected ortho or meta substitutedstarting material and vice versa. Similarly, other molecular changeswithin the scope of the invention are readily made.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds, compositions, orprocedures shown and described, as obvious modifications and equivalentswill be apparent to one skilled in the art, and the invention istherefore to be limited only by the scope of the appended claims.

We claim:
 1. A compound selected from the group consisting of (a) apyrrolidinoethylamine amide of the formula: ##STR31## wherein ##STR32##is an acyl radical of 9-fluorenecarboxylic acid, and (b) apharmaceutically acceptable acid addition salt thereof.
 2. Compound ofclaim 1 which is N(2'-pyrrolidinoethyl)-9-fluorenecarboxamide acidaddition salt.
 3. Acid addition salt of claim 2, which is thehydrochloride.
 4. A pharmaceutical composition suitable for use in thealleviation of cough, comprising a compound of claim 1, in an amounteffective for said purpose, in association with a pharmaceuticalcarrier.
 5. Composition of claim 4, wherein the compound is an acidaddition salt.
 6. Composition of claim 4, wherein the compound is thehydrochloride.
 7. Method for the treatment of a patient suffering fromcough, comprising administering to the patient a compound of claim 1 inan amount effective for the alleviation of said condition.
 8. Method ofclaim 7, wherein the compound is an acid addition salt.
 9. Method ofclaim 7, wherein the compound is the hydrochloride.